6u3p: Difference between revisions
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<StructureSection load='6u3p' size='340' side='right'caption='[[6u3p]], [[Resolution|resolution]] 3.00Å' scene=''> | <StructureSection load='6u3p' size='340' side='right'caption='[[6u3p]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6u3p]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6u3p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U3P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U3P FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PQY:(2E,2E)-N,N-[1,4-diazepane-1,4-diyldi(ethane-2,1-diyl)]bis[2-(hydroxyimino)acetamide]'>PQY</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PQY:(2E,2E)-N,N-[1,4-diazepane-1,4-diyldi(ethane-2,1-diyl)]bis[2-(hydroxyimino)acetamide]'>PQY</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6u3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u3p OCA], [https://pdbe.org/6u3p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u3p RCSB], [https://www.ebi.ac.uk/pdbsum/6u3p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u3p ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/ACES_HUMAN ACES_HUMAN] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.<ref>PMID:2714437</ref> <ref>PMID:1748670</ref> <ref>PMID:1517212</ref> <ref>PMID:11985878</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6u3p" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6u3p" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Gerlits | [[Category: Gerlits O]] | ||
[[Category: Kovalevsky | [[Category: Kovalevsky A]] | ||
[[Category: Radic | [[Category: Radic Z]] | ||
Latest revision as of 10:43, 11 October 2023
Binary complex of native hAChE with oxime reactivator LG-703Binary complex of native hAChE with oxime reactivator LG-703
Structural highlights
FunctionACES_HUMAN Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.[1] [2] [3] [4] Publication Abstract from PubMedOrganophosphate (OP) intoxications from nerve agent and OP pesticide exposures are managed with pyridinium aldoxime-based therapies whose success rates are currently limited. The pyridinium cation hampers uptake of OPs into the central nervous system (CNS). Furthermore, it frequently binds to aromatic residues of OP-inhibited acetylcholinesterase (AChE) in orientations that are non-productive for AChE reactivation, and the structural diversity of OPs impedes efficient reactivation. Improvements of OP antidotes need to include much better access of AChE reactivators to the CNS and optimized orientation of the antidotes' nucleophile within the AChE active-center gorge. On the basis of X-ray structures of a CNS-penetrating reactivator, monoxime RS194B, reversibly bound to native and venomous agent X (VX)-inhibited human AChE (hAChE), here we created seven uncharged acetamido bis-oximes as candidate antidotes. Both oxime groups in these bis-oximes were attached to the same central, saturated heterocyclic core. Diverse protonation of the heterocyclic amines and oxime groups of the bis-oximes resulted in equilibration among up to 16 distinct ionization forms, including uncharged forms capable of diffusing into the CNS and multiple zwitterionic forms optimal for reactivation reactions. Conformationally diverse zwitterions that could act as structural antidote variants significantly improved in vitro reactivation of diverse OP-hAChE conjugates. Oxime group re-orientation of one of the bis-oximes, forcing it to point into the active center for reactivation, was confirmed by X-ray structural analysis. Our findings provide detailed structure-activity properties of several CNS-directed, uncharged aliphatic bis-oximes holding promise for use as protonation-dependent, conformationally adaptive, "smart" accelerated antidotes against OP toxicity. Rational design, synthesis and evaluation of uncharged, "smart" bis-oxime antidotes of organophosphate-inhibited human acetylcholinesterase.,Gorecki L, Gerlits O, Kong X, Cheng X, Blumenthal DK, Taylor P, Ballatore C, Kovalevsky A, Radic Z J Biol Chem. 2020 Feb 4. pii: RA119.012400. doi: 10.1074/jbc.RA119.012400. PMID:32019865[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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